Preservative free brimonidine and timolol solutions

ABSTRACT

The present invention is directed to preservative-free solutions of brimonidine and timolol for lowering intra-ocular pressure and treatment of glaucoma.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 13/812,599, filed Jan. 28, 2013, which is a national phase application under 35 U.S.C. § 371 of PCT Patent Application No. PCT/US2011/045656, filed Jul. 28, 2011, which claims priority to U.S. Provisional Patent Application Ser. No. 61/368,681, filed on Jul. 29, 2010, each of which are incorporated herein by reference in their entireties and serve as the basis of a priority and/or benefit claim for the present application.

FIELD OF THE INVENTION

The present application is directed to preservative-free formulations of brimonidine and timolol.

BACKGROUND OF THE INVENTION

Brimonidine tartrate is a selective and potent alpha-2 adrenergic agonist. Brimonidine lowers intraocular pressure by reducing aqueous humor production and increasing uveoscleral outflow. Timolol maleate is a non-selective beta adrenergic receptor blocking agent. Currently marketed brimonidine and timolol combination ophthalmic solution with preservative is indicated for the reduction of elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP.

Use of preservative containing eye drops has been implicated in the development or worsening of ocular surface disease. Management of open angle glaucoma and ocular hypertension require long term treatment with eye drops containing preservatives. Symptoms and signs of ocular surface disease such as ocular surface breakdown, irritation, burning, foreign body sensation, dryness, inadequate quantity of tears, etc. are prevalent in a large proportion of patients with open angle glaucoma and ocular hypertension.

Compared to eye drops preserved with benzalkonium chloride, preservative-free eye drops induce significantly fewer ocular symptoms and signs of irritation in patients, such as pain or discomfort, hyperemia, foreign body sensation, stinging or burning, and dry eye sensation.

Patients experiencing hypersensitivity reactions with benzalkonium chloride cannot use a commercial brimonidine and timolol products containing benzalkonium chloride which is preserved even with 0.005% w/v benzalkonium chloride. Benzalkonium chloride also may be absorbed by the soft contact lenses therefore patients wearing soft contact lenses are advised to remove lenses prior to administration and wait at least 15 minutes before reinserting them.

SUMMARY OF THE INVENTION

The present invention is directed to a brimonidine and timolol solutions without benzalkonium chloride or other preservatives which will be superior from a safety & tolerability standpoint while maintaining and/or improving its efficacy of IOP lowering and be available for use by patients hypersensitive to benzalkonium chloride and be convenient for patients wearing soft contact lenses.

Brimonidine and timolol ophthalmic solution without preservative is a clear, greenish-yellow, isotonic, sterile solution. The drug product contains brimonidine and timolol as the active ingredients. The inactive ingredients are tonicity and buffer agents, and purified water. Suitable buffers such as sodium phosphate dibasic heptahydrate and citric acid monohydrate and suitable tonicity agents such as sodium chloride may be included. The final solution would be an aqueous solution having a pH value within the range of about 6.5 to about 7.3, preferably 6.9 and osmolality in range of 260-220 mOsmol/kg.

The compositions of the present invention may be generally made according to the teachings of U.S. Pat. No. 7,323,463 which is hereby incorporated by reference in its entirety.

Certain embodiments of the present invention are described below:

-   -   1) A preservative free brimonidine and timolol composition for         lowering intraocular pressure in a human patient comprising the         following formulation: about 0.2% w/v brimonidine; about 0.5%         w/v timolol; about 2.15% w/v sodium phosphate dibasic         heptahydrate; water and at a pH of about 6.9.     -   2) A preservative free brimonidine and timolol composition for         lowering intraocular pressure in a human patient comprising the         following formulation: 0.2% w/v brimonidine; 0.5% w/v timolol;         about 2.15% w/v sodium phosphate dibasic heptahydrate;         hydrochloric acid, sodium hydroxide, and water and at a pH of         about 6.9.     -   3) The preservative free composition of paragraphs 1-2 wherein         the timolol is timolol maleate at 0.68% w/v and brimonidine is         brimonidine tartrate.     -   4) A composition as described in Table 1.     -   5) The composition of any of paragraphs 1-4 wherein the         composition is a solution and is useful for treating glaucoma.     -   6) The composition of any of paragraphs 1-4 wherein the         composition is a solution and is contained in a unit dose kit         form.     -   7) The composition of any of paragraphs 1-4 wherein the         composition is applied at least once a day.     -   8) The composition of paragraph 2 wherein the composition is         applied twice a day.     -   9) The composition of paragraphs 1 or 2 wherein the composition         has greater bioavailability of brimonidine and timolol in the         eye of the patient with fewer side-effects than brimonidine and         timolol preserved with benzalkonium chloride.     -   10) The composition of paragraphs 1 and 2 wherein the         composition is contained in a multi-dose vial which has         anti-preservative properties such as metal-ions imbedded in its         dispensing tip.     -   11) The composition of paragraph 12 wherein the metal ions are         silver ions.

DETAILED DESCRIPTION OF THE INVENTION

A brimonidine and timolol ophthalmic formulation of the present invention without preservative is shown in Table-1.

TABLE 1 Example of brimonidine and timolol ophthalmic solution without preservative according to the present invention: Ingredients Units Grade Amount Brimonidine Tartarate % w/v N/A 0.2 Timolol Maleate % w/v USP/Ph 0.68 Eur Sodium Phosphate Dibasic Heptahydrate % w/v USP 2.15 Sodium Phosphate Monobasic Monohydrate % w/v USP 0.43 Hydrochloric Acid % w/v USP/Ph pH 6.9 Eur Sodium Hydroxide % w/v USP/Ph pH 6.9 Eur Purified Water/Water for injection Q.S. USP/Ph QS Eur

The present invention is directed to formulations of brimonidine and timolol without benzalkonium chloride as a preservative. As a result of the removal of benzalkonium chloride, the present invention results in the same or greater bioavailability of the active ingredients bimatoprost and timolol in the eye without the unwanted side-effects associated with the preservative benzalkonium chloride which will improve efficacy of the product in lowering TOP per dosage unit, superior patient compliance and with fewer side-effects such as hyperemia. Other side effects which may be avoided include asthenia, blepharitis, corneal erosion, depression, epiphora, eye discharge, eye dryness, irritation, eye pain, eyelid edema, eyelid erythema, eyelid pruritus, foreign body sensation, headache, hypertension, oral dryness, somnolence, superficial pectate keratitis, and visual disturbance. 

The invention claimed is:
 1. A preservative free brimonidine and timolol composition for lowering intraocular pressure in a human patient comprising the following formulation: about 0.2% w/v brimonidine tartrate; about 0.68% w/v timolol maleate; about 2.15% w/v sodium phosphate dibasic heptahydrate; about 0.43% w/v sodium phosphate monobasic heptahydrate and water wherein the preservative free brimonidine and timolol composition dosed twice a day lowers intraocular pressure to a greater degree as compared to a second composition dosed twice a day comprising about 0.2% w/v brimonidine tartrate; about 0.68% w/v timolol maleate; about 0.005% benzalkonium chloride; about 2.15% w/v sodium phosphate dibasic heptahydrate; about 0.43% w/v sodium phosphate monobasic heptahydrate and water.
 2. A preservative free brimonidine and timolol composition for lowering intraocular pressure in a human patient comprising the following formulation: 0.2% w/v brimonidine tartate; 0.68% w/v timolol maleate; about 2.15% w/v sodium phosphate dibasic heptahydrate; about 0.43% w/v sodium phosphate monobasic heptahydrate; hydrochloric acid, sodium hydroxide, and water and at a pH of about 6.9 wherein the preservative free brimonidine and timolol composition dosed twice a day results in fewer side effects of one selected from the group consisting of ocular pain, hyperemia, foreign body sensation, stinging or burning and dry eye sensation as compared to a second composition dosed twice a day comprising about 0.2% w/v brimonidine tartrate; about 0.68% w/v timolol maleate; about 0.005% benzalkonium chloride; about 2.15% w/v sodium phosphate dibasic heptahydrate; 0.43% w/v sodium phosphate monobasic heptahydrate, hydrochloric acid, sodium hydroxide and water and at a pH of about 6.9.
 3. The preservative free composition of claim 1 wherein the timolol maleate is at 0.68% w/v.
 4. A composition for use in the treatment of elevated intraocular pressure or glaucoma in a patient suffering therefrom comprising about 0.2% w/v brimonidine tartrate; about 0.68% w/v timolol maleate; about 2.15% w/v sodium phosphate dibasic heptahydrate; about 0.43% w/v sodium phosphate monobasic heptahydrate; hydrochloric acid, sodium hydroxide and water and at a pH of about 6.9 wherein the composition is preservative free.
 5. The composition of claim 1 wherein the composition is a solution and is useful for treating glaucoma.
 6. The composition of claim 1 wherein the composition is a solution and is contained in a unit dose kit form.
 7. The composition of claim 4 wherein the composition is applied at least once a day.
 8. The composition of claim 4 wherein the composition is applied at least twice a day.
 9. The composition of claim 1 wherein the composition has greater bioavailability of brimonidine and timolol in the eye of the patient with fewer side-effects than brimonidine and timolol preserved with benzalkonium chloride.
 10. A method of lowering intraocular pressure in a patient suffering from elevated intraocular pressure by administering the preservative free composition of claim
 1. 11. The composition of claim 2 wherein the preservative free composition dosed twice a day results in less hyperemia in the patient as compared to the composition preserved with brimonidine tartrate.
 12. The composition of claim 2 wherein the preserved composition dosed twice a day results in less burning and stinging in the patient as compared to the composition preserved with brimonidine tartrate.
 13. The composition of claim 2 wherein the preserved composition dosed twice a day results in less dry eye in the patient as compared to the composition preserved with brimonidine tartrate.
 14. The composition of claim 4 wherein the composition is a solution.
 15. The composition of claim 4 wherein the preserved composition has better efficacy in a patient as compared to the same composition preserved with 0.005% w/v benzalkonium chloride when both compositions are applied twice a day.
 16. The composition of claim 15 wherein the preserved composition lowers intraocular pressure to a greater degree as compared to the same composition preserved with 0.005% w/v benzalkonium chloride when both compositions are applied twice a day.
 17. The composition of claim 15 wherein the preserved composition results in fewer side effects as compared to the same composition preserved with 0.005% w/v benzalkonium chloride. 